Cyclic-di-AMP modulates cellular turgor in response to defects in bacterial cell wall synthesis

Cyclic-di-AMP (c-di-AMP) is an essential second messenger in Bacillus subtilis and many other Gram-positive bacteria. Work over the past decade has revealed that this cyclic nucleotide controls cation and osmolyte transporters, leading to the hypothesis that c-di-AMP regulates cytoplasmic turgor pressure. Although the targets of c-di-AMP are well established, the signals that control the levels of this second messenger and the factors that transduce these signals are unknown. Here we report that c-di-AMP levels are modulated by the cyclase regulator CdaR in response to cell wall defects. We further demonstrate that changing the levels of c-di-AMP alters turgor pressure. Our data support a model in which CdaR senses defects in the cell wall and activates c-di-AMP synthesis in response. The increase in c-di-AMP reduces turgor, preventing lysis and enabling fortification of the peptidoglycan meshwork. Thus, a central function of c-di-AMP is to control cellular turgor in response to envelope defects.